The invention relates to the field of natural plant derived ingredients which have beneficial properties to health. More particularly the invention relates to ingredients derived from the Indian plant Commiphora mukul and their novel use in addressing the human condition of insulin resistance and health problems associated therewith.
Insulin is a hormone well known to play a key role in maintaining blood glucose levels within healthy parameters. Where the action of insulin is impaired, as is the case in the human condition insulin resistance, a range of health problems can occur. In the short term the health problems associated with insulin resistance comprise chronic fatigue, cognitive impairment and mood swings, whilst long term they include more chronic diseases such as cardiovascular disease, type-II diabetes and polycystic ovary syndrome. Insulin resistance is therefore a complex metabolic condition and the frequency of incidence within the human population makes it highly desirable to develop a means by which it can be controlled or prevented.
PPARgamma is a known member of the peroxisome proliferator activated receptor (PPAR) subset of the nuclear hormone receptor superfamily. It is a ligand activated transcription factor and binds DNA in a heterodimeric complex with a second nuclear hormone receptor RXR. PPARgamma has been characterised as an important regulator of lipid metabolism. PPARgamma is suggested as playing a role in insulin sensitivity and other biological activities including effects on inflammation, cancer, cognition and cellular differentiation.
Commiphora mukul has long been used as a herbal treatment for hyperlipidaemia in the form of a gum resin called xe2x80x9cguggulipidxe2x80x9d or xe2x80x9cguggal lipidxe2x80x9d, however little is known in the art about the effect of this plant at a molecular level. EP 0997149 discloses that the pharmacological activity of guggulipid is attributable to known ketonic steroids the E- and Z-guggulsterones, however contrary to expectation, the pharmacological activity of guggulipid with respect to PPARgamma receptor activity has been found by the applicants not to be attributable to these guggulsterones.
Guggulipid has been disclosed as an agent for the treatment of autoimmune diseases by virtue of its anti-inflammatory effect. In this context the autoimmune form of diabetes i.e. type-1 has been noted. Guggulipid has also been included in compositions for dietary supplementation (EP997149).
Insulin resistance is a causative agent of type-2 diabetes and is distinct from the autoimmune type-1 form. At the time of filing the influence of guggulipid on human insulin resistance and in particular the influence of guggulipid on PPARgamma receptors was not known.
The objective technical problem to be solved by the present invention is to provide food compositions comprising naturally derived ingredients which are capable of inducing human health benefits by the treatment and/or prevention of insulin resistance. In particular the invention addresses the problem of providing natural ingredients which are capable of treating or preventing insulin resistance by activating PPARgamma receptors.
The applicants have found that compounds present in the natural plant extract guggulipid offer a novel solution to the defined problem, thereby providing naturally derived ingredients capable of treating and/or preventing insulin resistance via PPARgamma receptor activation.
The prior art is silent as to any suggestion that a guggulipid extract may have PPARgamma activating properties and the applicants are aware of no connection having been established in the art between guggulipid or its components and insulin sensitivity.
The problem of providing food compositions which treat and/or prevent insulin resistance in humans has now been solved by providing in a first object of the invention, a food composition for the treatment and/or prevention of insulin resistance in humans comprising an effective amount of a compound according to the formula; 
wherein,
R1 is selected from the group consisting of COOH, CH2OH including salts and/or esters thereof and CH3; and
R2 is selected from the group consisting of OH, O and esters thereof;
wherein said compound is contained within continuous or discontinuous fat phase.
It is a second object of the invention to provide a food composition for the treatment and/or prevention of insulin resistance in humans comprising an effective amount of a compound according to the formula described above wherein said compound is contained within a continuous or discontinuous aqueous phase.
A preferred embodiment comprises a food composition as described above wherein said compound is present in an amount of at least 0.01% by weight.
It is a third object of the invention to provide a food composition for the treatment and/or prevention of insulin resistance in humans wherein said composition comprises a compound as described above in an amount of at least 3% by weight.
In a fourth object the present invention provides food composition according as described above for use in the treatment and/or prevention of diseases selected from the group comprising polycystic ovary syndrome, type-2 diabetes, gestational diabetes, syndrome X, hypertension, psoriasis and stroke.
A fifth object of the invention provides a food composition according to any one of claims 1 to 4 for use in the treatment and/or prevention of one or more symptoms of insulin resistance selected from the group comprising reduced energy levels, reduced cognitive performance, tiredness and mood swings.
In a preferred embodiment the food composition of the invention is preferably, selected from the group comprising edible spreads, mayonnaise, dressing, ice cream, dairy and non-dairy creams, confections, bakery products, soups, beverages, jam, cakes, chocolate, dietary supplements, sauces and speciality foods for type-2 diabetics.
Conventional fractions of the commercially available guggulipid extract which have been processed for food compositions have an undesirable bitterness and accordingly are unpleasant to taste. In contrast neither compounds identified by the invention nor fractions of the guggulipid extract which have been enriched for these compounds have the bitterness associated with conventional fractions of the guggulipid extract.
Particular advantage is therefore offered by incorporating either the compounds according to formula I or a fraction of guggulipid extract enriched for such compounds into a food composition. In this way the favourable health benefits are maintained with no flavour detriment.
A sixth object of the invention therefore provides for the use of a fraction of a guggulipid extract in the manufacture of a food composition for the treatment and/or prevention of insulin resistance wherein said fraction comprises at least 15 wt % of a compound according to claim 1 and less than 1.0 wt % of Z and E guggulsterones;
It has also been found that crude guggulipid extract may induce dehydration, however, these effects can be avoided by applying the novel guggulipid fractions of the guggulipid extract provided herein which are enriched for one or more compounds according to formula I in place of the crude guggulipid extract.
It is therefore a seventh object of the invention to provide a blend of a guggulipid fraction and another component wherein said blend comprises;
(i) a guggulipid fraction comprising more than 15 wt %, compound according to formula I, and;
(ii) tri and/or diglycerides including fatty acids and their esters, in such amounts that the blend contains at least 2 wt % of the guggulipid fraction.
Preferably the guggulipid fraction used in the manufacture of a food composition and in the blend will comprise more than 20 wt %, more preferably more that 40 wt %, most preferably more than 60 wt % of a compound according to the formula I.
In a most preferred embodiment the invention comprises a blend as described above wherein the compound according to formula I is 13-(decahydro-2-hydroxy-2,5,5,8a-tetramethyl-6-oxo-1-naphthalenyl)-2,6,10-trimethyl-tridecatrienoic acid.
Conjugated linoleic acid (CLA) is known in the art for use in body weight management, however it has been found that under certain circumstances this may have the effect of reducing insulin sensitivity in some humans. This effect can be countered by combination of CLA in a blend with an effective amount of a guggulipid fraction according to the invention or compound according to formula I.
A further preferred embodiment of the invention therefore comprises a blend comprising a guggulipid fraction and another component wherein the guggulipid fraction is the fraction as described above and the other component is a compound with at least 40 wt % CLA in it, whereby the CLA can be present as free fatty acid, as tri-or partial glyceride or as alkyl ester of CLA and whereby the blend contains at least 20 wt % CLA residues.
The application of a crude guggulipid extract for the treatment and/or prevention of insulin resistance suffers the disadvantage that the crude extract may cause dehydration in some consumers. Through the application of guggulipid fractions identified herein the invention provides a method for treating and/or preventing insulin resistance either inherent to the consumer or associated with CLA consumption, wherein said consumer is administered an effective amount of a guggulipid fraction described above, or a blend as described above.
An embodiment of the invention is also directed to food compositions comprising a blend as described above.
An eighth object of the invention provides a compound according to formula I for use as a medicament.
Via activation of a PPARgamma receptor a compound according to formula I has a positive effect of reducing insulin resistance. The invention therefore preferably embodies either guggulipid extract or a compound according to according to formula I for use in the treatment and/or prevention of insulin resistance in humans.
Insulin resistance has a large number of associated disorders in humans and as a result a compound according to formula I has widespread health benefits. In a further preferred embodiment the invention is therefore directed to a compound according to formula I for use in the treatment and/or prevention of one or more diseases selected from the group comprising polycystic ovary syndrome, type-2 diabetes, gestational diabetes, syndrome X, hypertension, psoriasis and stroke.
Since insulin resistance is a key cause of diabetes type-2 a preferred embodiment of the invention relates to a use as described above for the treatment and/or prevention of type-2 diabetes.
The associated disorders of insulin resistance have a number of common symptoms, therefore in a further preferred embodiment the invention is directed to a compound according to formula I for use in the treatment and/or prevention of one or more symptoms of insulin resistance selected from the group comprising reduced energy levels, reduced cognitive performance, tiredness, spatial disorientation, clinical depression and mood swings.
An ninth object of the invention provides a compound according to formula 1 for use in the manufacture of a composition, preferably a food composition, for the treatment and/or prevention of insulin resistance in humans.
Preferably the invention embodies a compound according to formula I for use in the manufacture of a composition for the treatment and/or prevention of one or more diseases selected from the group comprising polycystic ovary syndrome, type-2 diabetes, gestational diabetes, syndrome X, hypertension, psoriasis and stroke.
A further preferred embodiment relates to a compound according to formula I for use in the manufacture of a composition for the treatment and/or prevention of one or more symptoms of insulin resistance selected from the group comprising reduced energy levels, reduced cognitive performance, tiredness, spatial disorientation and clinical depression.
Guggulipid extract is used herein to refer to a solvent extract of guggulipid gum resin, however it is recognised that other starting materials derived from the Commiphora mukul plant may be used. Extraction from the gum resin may be performed with any suitable solvent, however it is preferable that ethyl acetate is used as this has been found to be a particularly effective solvent. A suitable guggulipid extract is commercially available from Indena as Gukkaselect(trademark).
In a compound according to formula I where R1 is COOH, an ester thereof will preferably comprise a linear or branched, substituted or unsubstituted alkyl group containing from 1 to 32 carbon atoms. Most preferred where R1 is COOH, esters thereof preferably contain an alcohol group containing from 1 to 12 carbon atoms (including C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11 and C12 alcohol groups).
Where R1 or R2 comprises an OH group esters thereof preferably comprise an acid group containing from 1 to 22 carbon atoms, most preferred from 6 to 18 carbon atoms (including C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17 and C18 acid groups.)
Preferably when R1 is COOH, R2 is O and most preferably the compound is in the form of a 13-(decahydro-2-hydroxy-2,5,5,8a-tetramethyl-6-oxo-1-napthalenyl)-2,6,10-trimethyl-2,6,10-Tridecatrienoic acid for example 13-(decahydro-2-hydroxy-2,5,5,8a-tetramethyl-6-oxo-1-napthalenyl)-2,6,10-trimethyl-[1R-[1xcex1(2E,6E,10E)2xcex2,4xcex2,8axcex1]]-2,6,10-Tridecatrienoic acid (9Cl) also known as commipherin or commipheric acid.
Preferably when R1 is CH2OH, R2 is O or OH. Most preferably R2 is O and the compound is in the form of a octahydro-6-hydroxy-5-(13-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienyl)1,1,4a,6-tetramethyl-2(1H)-naphthalenone, for example octahydro-6-hydroxy-5-(13-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienyl)-1,1,4a,6-tetramethyl-[4aS-[4axcex1,5xcex1(3E,7E,11E),6xcex2,8axcex2]]-2(1H)-naphthalenone also known as commipherol.
Preferably when R1 is CH3, R2 is OH and the compound is preferably decahydro-1,1,4a,6-tetramethyl-5-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-,(4aS,5R,6R,8aR)-2,6-Naphthalenediol.
It has been found that commipheric acid is particularly effective in reducing insulin resistance in humans therefore in a most preferred embodiment the compound according to formula I is commipheric acid.
It is appreciated that a plurality of compounds according to the above defined formula may be suitably incorporated into a composition of the invention to provide an effective amount thereof. Accordingly the singular usage of xe2x80x98axe2x80x99 compound in this description is taken to encompass such a plurality of compounds in combination within a composition of the invention.
Where a food composition according to present invention comprises a compound according to formula I within a fat phase thereof, this fat phase may be continuous or discontinuous. In certain products such as a margarine, the compound is suitably provided in the continuous fat phase therein. For a continuous fat phase system a food composition of the present invention preferably comprises at least 5 wt % fat, preferably less than 90 wt % fat, more preferably the fat component of the composition comprises from 20 to 80 wt % fat, most preferably from 30 to 50 wt % fat.
In alternative systems such as those found in sauces, soups, dressings, meal replacement bars, mayonnaise, dairy/non-dairy cream or ice cream etc. the compound of formula I is more likely to be present in a discontinuous fat phase, either as an oil in water emulsion or within discrete solid fat droplets.
Oil in water emulsions in accordance with the present invention preferably use emulsifiers with HLB values in the range 8 to 18 and/or polymeric stabilisers. The person skilled in the art will be aware of emulsifiers that fall within this HLB range. Suitable food grade emulsifiers and stabilisers used for preparation of oil in water emulsions may be selected from one or more of the group comprising lecithins (phospholipids), sodium caseinate, gum arabic, deacetylated tartaric esters of monoglycerides (DATEM), sucrose esters of fatty acids, polyglycerol esters of fatty acids (PGE), polysorbate 60, polysorbate 65 and polysorbate 80.
The amount of emulsifier and/or stabiliser used in a oil in water composition will depend on the droplet size, the relative phase volumes and stability of emulsion required. Typically the amount will range from 1 to 10 wt %, but may for particular examples range from 0.5 to 30 wt %.
The fat content of a product with a discontinuous fat phase can vary widely depending on the nature of the product. A product such as mayonnaise will typically contain around 85 wt % fat whereas a sauce such as tomato sauce may contain 0.1 wt % fat. Preferably products with a discontinuous fat phase comprise at least 0.1 wt % fat, preferably less than 90 wt % fat, more preferably the fat component of the composition comprises from 5 to 50 wt % fat, most preferably from 10 to 20 wt % fat.
A meal substitute such as a meal replacement bar will suitably comprise a compound as described above wherein said compound is provided within a discontinuous oil phase.
Compounds according to the formula I are poorly soluble in aqueous conditions, hence dispersal of the compound in an aqueous phase has been found to be most effectively achieved through the use of one or more carrier molecules. Such carrier molecules are preferably food grade emulsifiers with HLB values in the range 8 to 18, more preferably one or more selected from the group comprising comprising lecithins (phospholipids), sodium caseinate, gum arabic, deacetylated tartaric esters of monoglycerides (DATEM), sucrose esters of fatty acids, polyglycerol esters of fatty acids (PGE), polysorbate 60, polysorbate 65 and polysorbate 80
Oil in water emulsion compositions according to the present invention may suitably be spray dried by conventional techniques known to the person skilled in the art to give powder supplements which may be added to other food compositions, in particular beverages. Powdered sodium caseinate oil in water emulsions are preferably provided in powdered form.
Powders have been produced by a process wherein Dynasan 118 (Stearic acid triglyceride, SASOL) containing 10 wt % of guggul or enriched commipheric acid was melted at 90xc2x0 C. with stirring. The material was then cooled quickly to xe2x88x9218xc2x0 C., placed in a blender with some pellets of dry ice, and ground into a fine powder.
The provision of such aqueous based systems allows the compounds of interest to suitably incorporated into low or non-fat containing products such as beverages, meal replacement drinks, soups and sauces.
The determination of an effective amount of the compound according to formula I within a food composition according to the present invention will depend on the amount of the food composition that is to be consumed within a daily period. Individual human consumption of one or more food compositions according to the invention should comprise sufficient compound to provide a average daily dosage of from 0.1 to 5 grams. Preferably daily consumption ranges from 0.5 to 2 grams, most preferred 1.0 to 1.5 grams to achieve the desired effect on insulin resistance.
The present invention provides novel food compositions wherein an effective compound as described above is provided in an aqueous or a fat phase. Preferably an effective amount is greater than 0.01 wt % of the consumed food composition, more preferably less than 20 wt %, most preferred between 0.1 wt % and 5 wt %.
The amount of daily consumption of a spread type product such as a margarine is comparatively low hence the extent of supplementation is preferably quite high. Such products may be suitably supplemented with a compound as defined above to at least 0.3 wt %, preferably less than 20 wt %, more preferred from 0.5 to 10 wt %. In a most preferred embodiment such products comprise a compound as defined above in an amount from 1 to 5 wt %.
In contrast the amount of daily consumption of beverage may be considerably higher than that of a spread and hence in such an embodiment of the invention is suitably supplemented with a compound as defined above to at least 0.01 wt % of the beverage as consumed. Dilutable concentrates would be supplemented to a level which achieves at least 0.01 wt % of the beverage when diluted for consumption. Preferably the supplementation of a beverage according to the invention is less than 0.5 wt % of the beverage as consumed, most preferably supplementation is within the range from 0.05 to 0.2 wt %. Ready to drink tea may suitably be supplemented in accordance with this regime.
Food compositions such as soups preferably comprise a compound as described above in an amount from 0.01 to 2.5 g per serving. Typically such compositions will comprise at least 0.03 wt % of said compound, preferably less than 2 wt %, more preferred from 0.1 to 1 wt %, most preferred from 0.25 to 0.5 wt %.
Where the food composition is a meal replacement bar or meal replacement drink, this is ideally supplemented with an amount of compound according to the above description of at least 0.03 and less than 1.6 grams per bar or drink, preferably from 0.1 to 1.0 grams, most preferred from 0.25 to 0.5 grams per bar or drink.
Through the consumption of one or more of the food compositions according to the invention the consumer may ensure that a dosage of from 0.1 to 5 grams of compound is ingested. By combining different food compositions as disclosed herein the consumer can gain a varied diet while ensuring the treatment and/or prevention of insulin resistance. An embodiment of the invention therefore comprises a combination of food compositions as described above for the treatment and/or prevention of insulin resistance in humans, wherein said combination is dictated by a predetermined diet plan.
The present invention also provides a novel food composition for the treatment and/or prevention of insulin resistance in humans wherein said composition comprises at least 3 wt % of a compound according to the above description. Compositions known in the art which contain crude guggulipid extract do not provide such levels of the active compounds identified herein and so do not have the ability as provided herein to influence insulin sensitivity. Preferably food compositions which comprise at least 3 wt % of a compound according to the above description are provided in the form of nutritional supplements such as capsules, tablets or powders.
Identifying those compound within guggulipid extract which activate PPARgamma involved the strategy illustrated in FIG. 1. Fractionation of the guggulipid extract is preferably performed initially by silica gel column fractionation with any subsequent sub-fractionation being preferably conducted by HPLC. Fractions and sub-fractions are analysed using a reporter gene assay to determine which has been enriched for molecules capable of activating PPARgamma. Additional cycles of the sub-fractionation process may be performed until no further enrichment for PPARgamma activating molecules can be detected. The final sub-fractions may then be characterised using structural techniques e.g. GCMS analysis.
PPARgamma receptor activity is determined by a suitable reporter gene assay. Preferably the reporter gene assay used comprises the transcription induction of a luciferase gene. Levels of firefly luciferase (normalised against the renilla luciferase control) provide a measure of reporter gene activity which in turn reflects the level of activation.
In a preferred embodiment the invention therefore provides a process for identifying compounds capable of activating a PPARgamma receptor wherein said process comprises the steps;
(i) fractionating a guggulipid extract;
(ii) selecting a fraction with PPARgamma receptor activity;
(iii) optionally repeating steps (i) and (ii) until no further increase in PPARgamma receptor activity in said fraction is observed;
CLA is known to display a number of health benefits such as weight control, fat control, muscle mass, etc but we have also found that sometimes CLA may also have a negative impact on insulin resistance. Intake of the guggulipid extract may alleviate these negative effects, but give rise to the further effect of dehydration. Fractions of the extract provided by the above process and most particularly the compounds according to formula I are able to alleviate the insulin resistance effect of CLA without giving rise to dehydration.